WO2006088716A1 - Tetralines substituees utilisees comme antagonistes selectifs du recepteur d'oestrogenes beta - Google Patents

Tetralines substituees utilisees comme antagonistes selectifs du recepteur d'oestrogenes beta Download PDF

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WO2006088716A1
WO2006088716A1 PCT/US2006/004540 US2006004540W WO2006088716A1 WO 2006088716 A1 WO2006088716 A1 WO 2006088716A1 US 2006004540 W US2006004540 W US 2006004540W WO 2006088716 A1 WO2006088716 A1 WO 2006088716A1
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preparation
methoxy
compound
phenyl
nmr
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PCT/US2006/004540
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English (en)
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Venkatesh Krishnan
Julian Stanley Kroin
Bryan Hurst Norman
Elizabeth Marie Thomas
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Eli Lilly And Company
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Priority to EP06720533A priority Critical patent/EP1853578A1/fr
Priority to US11/814,806 priority patent/US8093302B2/en
Publication of WO2006088716A1 publication Critical patent/WO2006088716A1/fr

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    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the present invention relates to novel tetralin ER- ⁇ agonist compounds, pharmaceutical compositions thereof, and use of these compounds to treat a ER- ⁇ mediated disease such as benign prostatic hypertrophy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, and arthritis.
  • a ER- ⁇ mediated disease such as benign prostatic hypertrophy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, and arthritis.
  • ER estogen receptor
  • ER- ⁇ is cloned from a rat prostatic cDNA library and is present in murine and human prostates. Consequently, the previously known ER is now designated as ER- ⁇ .
  • ER- ⁇ and ER- ⁇ share high amino acid homology, have similar 17- ⁇ Estradiol (E2) binding affinities, and can hetero- or homodimerize to form a signaling complex. See, e.g., Kuiper GG, et al., Endocrinol.
  • 3-Beta, 17-beta-androstanediol is a major metabolite of dihydrotestosterone (DHT), the 5-alpha-reduced active intracellular androgen in male accessory sex organs.
  • DHT dihydrotestosterone
  • ER- ⁇ activation also stimulates increased glutathione S-transferase and quinone reductase expression.
  • These two enzymes have been shown to possess chemoprotective detoxification properties; Chang WY et al., Prostate 40: 115-24 (1999); Montano MM et al., J. Biol. Chem. 273: 25443-9 (1998).
  • ER-selective modulators would similarly possess significant clinical utility. Since ER- ⁇ is strongly expressed in a number of tissues including prostate, bladder, ovary, testis, lung, small intestine, vascular endothelium, and various parts of the brain, compounds that selectively modulate ER- ⁇ have been suggested as being useful in the treatment of a variety of disease conditions, such as obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, and arthritis. See e.g., J.
  • ER- ⁇ agonists will display different therapeutic profiles compared to ER- ⁇ antagonists or agonists, and would be preferentially beneficial in tissues relying on ER- ⁇ signaling.
  • the prostate gland produces components that are found in the semen and blood. Some of these are regulatory peptides.
  • the prostate gland comprises stroma and epithelium cells, the latter group consisting of columnar secretory cells and basal non- secretory cells.
  • the proliferation of these basal cells, as well as stroma cells gives rise to benign prostatic hyperplasia (BPH), which is one common prostate disease.
  • BPH benign prostatic hyperplasia
  • Consequences of BPH can include hypertrophy of bladder smooth muscle, decompensated bladder, and increased incidence of urinary tract infection.
  • the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70.
  • Drag treatment for BPH currently employs alpha andrenergic antagonists for symptomatic relief or steroid 5-alpha reductase inhibitors to reduce hyperplastic tissue bulk. Because these approaches are of limited therapeutic benefit, new therapies are needed.
  • G is -CH 2 -, -CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 - or -O-;
  • R 1 is hydrogen, hydroxy or amino
  • R is hydrogen or hydroxy
  • R 3 is hydrogen, hydroxy, Br, methyl, n-propyl, i-propyl, n-butyl, hydroxymethyl, methoxy, CH 3 CH(OH)-, acetyl, CH 3 OCH 2 -, R 7 C(O)CH 2 CH 2 - Or R 8 CH 2 CH 2 CH 2 -; or R 2 and R 3 form a -CH 2 CH 2 -X-O- biradical, wherein the oxygen radical represents the R 2 end and the methylene radical represents the R 3 end;
  • R 4 is hydrogen, hydroxy, cyano, R 9 -CH 2 -, vinyl, 4-chlorophenyl, carboxy, aminocarbonyl or methoxycarbonyl;
  • R 5 is hydrogen, methyl, ethyl, R 10 -CH 2 -, CH 3 CH(OH)-, acetyl, carboxyl or methoxycarbonyl;
  • R 6 is hydrogen or fluoro
  • R 7 is amino, methylamino, dimethylamino or piperidin-1-yl
  • R is bromo, hydroxy, dimethylamino or methoxy
  • R 9 is bromo, cyano, hydroxy, methoxy or azido
  • R 10 is bromo, hydroxy, cyano, methoxy or pyrrolidin-1-yl; with the provisos that: at least one or R 1 , R 2 , R 3 and R 4 is hydroxy and at least three of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and enantiomers thereof.
  • the compound is of Formula Ia:
  • the compound is of formula Ia and G is -CH 2 -
  • the compound is of formula Ia and G is -O-.
  • the compound is of formula Ia and G is -CH 2 -CH 2 -:
  • the compound is of formula Ia and G is -CH 2 C(CH 3 ) 2 -.
  • the compound is of formula Ib:
  • the compound is of formula Ib and R 3 is R 7 C(O)CH 2 CH 2 -.
  • the compound is of formula Ib and R 3 is R 8 CH 2 CH 2 CH 2 - or hydroxymethyl. In another specific embodiment, the compound is of Formula Ic:
  • the compound is of Formula Id:
  • the compound is of Formula Ie:
  • the compound is of Formula If:
  • the compound is of formula Ig:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of Formula I, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method of treating nocturia, obstructive uropathy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis, or benign prostatic hypertrophy in a patient, comprising: administering to said patient an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • condition being treated is benign prostatic hypertrophy.
  • condition being treated is prostate cancer.
  • the present invention provides a method of treating nocturia, uropathy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis or benign prostatic hypertrophy in a patient, comprising: administering to said patient a pharmaceutical composition comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • condition being treated is benign prostatic hypertrophy.
  • condition being treated is prostate cancer.
  • the present invention provides the use of a compound, or pharmaceutically acceptable salt thereof, of Formula I for the manufacture of a medicament for the treatment of nocturia, uropathy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis, or benign prostatic hypertrophy.
  • the medicament is for the treatment of benign prostatic hypertrophy.
  • the medicament is for the treatment of prostate cancer.
  • the present invention provides a method of agonizing ER- ⁇ receptor function, comprising: contacting the receptor with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of agonizing ER- ⁇ receptor function in a patient, comprising: administering to said patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating ER- ⁇ mediated disease condition in a patient, comprising: administering to said patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the condition is nocturia, obstructive uropathy, obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis, or benign prostatic hypertrophy.
  • condition is benign prostatic hypertrophy.
  • the condition is prostate cancer.
  • C 1 -C 4 alkyl refers to a branched or straight chained alkyl radical containing from 1 to 4 carbon atoms, such as methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec butyl (s-Bu) or tert-butyl (t-Bu);
  • C 2 -C 4 alkenyl refers to a straight or branched hydrocarbon chain of 2 to 4 carbon atoms with at least one carbon-carbon double bond.
  • C 2 -C 4 alkenyl groups include, but are not limited to, ethenyl (vinyl), propen- 1-yl, propen-2-yl (isoprenyl), propen-3-yl (allyl), 2-methyl ⁇ propen-3-yl, 2-buten-4-yl, 2- methyl-propen-1-yl, and 1-buten-l-yl; c) the term "C 2 -C 4 alkynyl" refers to a straight or branched hydrocarbon chain of 2 to 4 carbon atoms with at least one carbon-carbon triple bond.
  • C 2 -C 4 alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl (isoprynyl), propyn-3-yl, 2-methyl-propyn-3-yl, 2-butyn-4-yl, 2-methyl-propyn-l-yl, and 1-butyn-l-yl; d) the terms “halo” and “halide” refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom; e) the designation " " " ⁇ " refers to a bond for which the stereochemistry is not designated; f) the designation " ""* " refers to a bond that protrudes forward out of the plane of the page; g) the designation " ' refers to a bond that protrudes backward out of the plane of the page; h) as used in the preparations and examples the following terms have the indicated meanings; "ng” refers
  • the terms "effective amount” and "therapeutically effective amount” of a compound of Formula (I) refer to an amount which is effective in controlling diseases and conditions associated with estrogen receptor-beta mediated diseases such as obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis or benign prostatic hypertrophy;
  • controlling diseases is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, but does include prophylactic treatment of the diseases and conditions associated with estrogen receptor-beta mediated diseases such as obesity, dementia, hypertension, incontinence, colon cancer, prostate cancer, infertility, depression, leukemia, inflammatory bowel disease, arthritis or benign prostatic hypertrophy; m) the term “pharmaceutically acceptable salts thereof” refers to either an acid addition salt or a basic addition salt; n) the term “pharmaceutically acceptable acid addition salts” is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (I).
  • Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include the mono-, di ⁇ , and tricarboxylic acids.
  • Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p- toluenesulfonic acid, and sulfonic acids such as benzenesulfonic acid, methanesulfonic acid, and 2-hydroxyethanesulfonic acid.
  • Such salts can exist in either a hydrated or substantially anhydrous form.
  • the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
  • pharmaceutically acceptable basic addition salts is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (I).
  • Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
  • Compounds of Formula I may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. AU asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • one optical isomer over its enantiomer a number of routes are available.
  • a mixture of enantiomers may be prepared, and then the two enantiomers may be separated.
  • a commonly employed method for the separation of a racemic mixture is the use of chiral high pressure liquid chromatography. Further details regarding resolution of enantiomeric mixtures may be found in J. Jacques, et al., Enantiomers, Racemates, and Resolutions, (1991).
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral phase gas chromatography, chiral- phase high performance liquid chromatography, or crystallizing the compound as a chiral salt complex, and resolutions may be performed at any stage or at the end of any step that is advantageous in the schemes below.
  • Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • Reaction of A with the phosphonium ylide results in the ⁇ , ⁇ -unsaturated ester, which isomerized under basic conditions to B.
  • Olefin hydrogenation under standard conditions H 2 , Pd on C gives the cis substituted product C.
  • This material (or related acid chloride) is cyclized using standard Friedel-Crafts conditions (Lewis acid) to give the tricyclic tetralone D.
  • This material is subjected to palladium catalyzed aryl coupling conditions to form the 2-aryl-l -tetralone E.
  • Ketone reduction to give alcohol F, followed by dehydration gave olefin G.
  • This material is reduced using catalytic hydrogenation to yield the all cis tetralin H.
  • Demethylation using boron tribromide provides the product bis phenol I.
  • AU products were isolated using techniques well known by those skilled in the art.
  • starting material H' is prepared according to Scheme 1. This material is either brominated to produce Q, or acetylated to produce R. Q is further substituted by conversion to the aryl lithium, followed by reaction with various reactive electrophilic agents, as are known to one skilled in the art. Both Q and R were subjected to various other functional group interconversions, known to those skilled in the art, to produce related compounds. These procedures are described in the experimental section. Intermediates S are demethylated with boron tribromide, as previously described, to produce bis phenol T.
  • starting material E is prepared according to Scheme 1. This material is converted to vinyl triflate U and then converted to ester V via palladium catalyzed carbonylation chemistry. Compound V is hydrogenated using palladium black to give W. The ester functionality in intermediate W is used to provide various substituted analogs X, using chemistry known to one skilled in the art. Final bis phenols Y were prepared using standard boron tribromide deniethylation conditions, as preciously described.
  • Preparation 13 is prepared from preparation 12 in a manner similar to preparation 3.
  • Preparation 15 is prepared from preparation 14 in a manner similar to preparation 6.
  • Preparation 16 is prepared from preparation 15 in a manner similar to preparation 7.
  • Preparation 17 is prepared from preparation 16 in a manner similar to preparation 8.
  • Preparation 18 is prepared from preparation 17 in a manner similar to preparation 9.
  • Preparation 19 is prepared from cyclopentene oxide and l-bromo-3, 5- dimethoxybenzene in a manner similar to preparation 10.
  • Preparation 20 is prepared from preparation 19 in a manner similar to preparation 11.
  • Preparation 21 is prepared from preparation 20 in a manner similar to preparations 1 and 2.
  • Preparation 22 is prepared from preparation 21 in a manner similar to preparation 3.
  • Preparation 23 is prepared from preparation 22 in a manner similar to preparation 14. MS m/z 247 (M+l).
  • Preparation 24 is prepared from preparation 23 in a manner similar to preparation 6. MS m/z 353 (M+l).
  • Preparation 25 is prepared from preparation 24 in a manner similar to preparation 7.
  • Preparation 26
  • Preparation 26 is prepared from preparation 25 in a manner similar to preparation 8. MS m/z 337 (M+l).
  • Preparation 27 is prepared from preparation 26 in a manner similar to preparation 9.
  • 1 H NMR (DMSO): 12.10 (s, IH), 7.25 (t, IH, / 7.9 Hz), 6.80 (m, 3H), 4.00 (m, 3H), 3.74 (s, 3H), 3.46 (m, 2H), 2.82 (m, IH), 1.87 (m, 2H).
  • Preparation 32 is prepared from preparation 31 in a manner similar to preparation 5.
  • TLC Rf O.11 in 2: 1 hexanes:ethyl acetate.
  • Preparation 37 is prepared from preparation 5 and 4-bromo-2-fluoroanisol in a manner similar to preparation 6.
  • TLC Rf O.13 in 6:1 hexanes:ethyl acetate.
  • Preparation 39 Preparation 39
  • 1 H NMR (CDCl 3 ): 7.2 (m, 4H), 6.9 (m, 2H), 6.8 (m, IH), 4.8 (d, IH, 7 9.4 Hz), 3.8 (s, 6H), 3.2 (m, 2H), 2.2 (m, IH), 2.0 (m, IH), 1.9 (m, IH), 1.5 (m, 6H).
  • 1 H NMR (CDCl 3 ): 7.3 (m, 2H), 7.2 (m, IH), 6.9 (m, 2H), 6.7 (m, 2H), 6.4 (d, IH, 7 2.7 Hz), 3.9 (s, 3H), 3.8 (s, 3H), 3.3 (m, IH), 3.2 (m, IH), 2.1 (m, IH), 1.4 (m, 7H).
  • Preparation 55 is prepared from preparation 54 in a manner similar to preparation 1.
  • Preparation 56 is prepared from preparation 55 in a manner similar to preparation 2.
  • Preparation 57 is prepared from preparation 56 in a manner similar to preparation 3.
  • Preparation 58 is prepared from preparation 57 in a manner similar to preparation 4.
  • Preparation 59 is prepared from preparation 58 in a manner similar to preparation 5.
  • Preparation 60 is prepared from preparation 59 in a manner similar to preparation 6.
  • Preparation 61 is prepared from preparation 60 in a manner similar to preparation 7.
  • Preparation 62 is prepared from preparation 61 in a manner similar to preparation 8.
  • Preparation 63 is prepared from preparation 62 in a manner similar to preparation 9.
  • Preparation 69 is prepared from preparation 68 in a manner similar to preparation 4. (3.3g, 91%): 1 H NMR (CDCl 3 ) ⁇ 7.22-7.17 (m, IH), 6.79-6.71 (m, 3H), 3.79 (s, 3H), 2.50-2.22 (m, IH), 1.95-1.77 (m, 2H), 1.67-1.21 (m, 6H), 1.02 (s, 3H), 0.99 (s, 3H), 0.93 (s, IH).
  • Preparation 70 is prepared from preparation 69 in a manner similar to preparation 5. (1.3g, 41%): 1 H NMR (CDCl 3 ) ⁇ 8.01-7.99 (d, IH), 6.83-6.78 (dd, IH), 6.66-6.65 (d, IH), 3.86 (s, 3H), 3.03-2.98 (m, IH), 2.89-2.82 (m, IH), 2.52-2.49 (m, IH), 2.32-2.26 (m, IH), 1.94-1.87 (m, IH), 1.53-1.37 (m, 4H), 1.30-1.24 (m, IH), 1.09 (s, 3H), 0.94 (s, 3H).
  • Preparation 72 is prepared from preparation 71 in a manner similar to preparation 7. (0.8g, 72%): 1 H NMR (CDCl 3 ) 67.51-7.49 (d, IH), 7.12-7.19 (d, 2H), 6.94-6.91 (d, 2H), 6.81-6.78 (dd, IH), 3.83 (s, 3H), 3.81 (s,3H), 3.07-2.98 (m, IH), 1.65-1.49 (m, 7H), 1.43-1.18 (m, 3H), 1.03 (s, 3H), 0.93 (s, 3H).
  • Preparation 73 is prepared from preparation 72 in a manner similar to preparation 8. (0.7g, 92%)%): 1 H NMR (CDCl 3 ) ⁇ 7.33-7.31 (d, 2H), 7.02-6.99 (d, IH), 6.90-6.88 (d, 2H), 6.79 (m, IH), 6.70-6.67 (dd, IH), 6.47 (bs, IH), 3.83 (s, 3H), 3.82 (s, 3H), 3.09-2.99 (m, IH), 1.45-1.25 (m, 3H), 1.06-1.03 (m, 2H), 1.0 (s, 3H), 0.95-.89 (m, 2H), 082 (s 3H).
  • Preparation 74 is prepared from preparation 73 in a manner similar to preparation 9. (0.38g, 54%): 1 H NMR (CDCl 3 ) ⁇ 7.24-7.22 (d,2H), 7.11-7.05 (m, IH), 6.98-6.97 (m, IH), 6.90-6.88 (d, 2H), 6.72-6.69 (dd, IH), 3.82 (s,3H), 3.81 (s, 3H), 3.3-3.26 (m, IH), 2.81-2.75 (m, IH), 1.43-1.17 (m, 6), 1.11-.99 (m, 3H), 0.88 (s, 3H), 0.49 (s, 3H).
  • Preparation 76 is prepared from preparation 75 in a manner similar to preparation 64. (6.6g, 43 mmol)to give the title compound (5.8g, 87%) : 1 H NMR (CDCl 3 ) ⁇ 7.27- 7.24 (m, IH), 6.92-6.84 (m, 4H), 3.81 (s,3H), 2.45 (s, 2H), 2.43-2.42 (d, 2H), 1.11 (s, 6H).
  • Preparation 77 is prepared from preparation 76 in a manner similar to preparation 65. (5.8g, 99%): 1 H NMR (CDCl 3 ) ⁇ 7.27-7.24 (m, IH), 6.82-6.79 (dd, IH), 6.75-6.73 (d, IH), 6.70-6.69 (m, IH), 3.79 (s, 3H),3.53-3.48 (m, IH), 2.37-2.24 (m, 2H), 2.19-2.13 (m, 2H), 1.83-1.69 (m, 2H), 1.11 (s, 3H), 1.00 (s, 3H).
  • Preparation 78 is prepared from preparation 77 in a manner similar to preparation 66. (5.3g, 74%): 1 H NMR (CDCl 3 ) ⁇ 7.24-7.20 (m, IH), 6.77-6.69 (m, 3H), 5.19 (s, IH), 3.77 (s, 3H), 3.58 (s, 3H), 3.47-3.43 (d, IH), 3.28-3.24 (dd, IH), 2.06-2.01 (m, 2H), 1.94- 1.87(m, IH), 1.56-1.51(m, 2H), 1.03 (s, 3H), 0.91 (s, 3H).
  • Preparation 79 is prepared from preparation 78 in a manner similar to preparation 67. (4.8g, 100%): 1 B NMR (CDCl 3 ) 67.20-7.17 (m, IH), 6.76-6.68 (m, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 2.89 (s, 2H), 2.29-2.26 (t, 2H), 1.86 (s, 2H), 1.46-1.43(t, 2H), 0.95 (s, 6H).
  • Preparation 80 is prepared from preparation 79 in a manner similar to preparation 3. (2g, 99%): 1 H NMR (CDCl 3 ) ⁇ 7.21-7.17 (t, IH), 6.83-6.81 (d, IH), 6.79-6.79 (t, IH), 6.75-6.73 (dd, IH), 2.96-2.92 (m, IH), 2.56-2.48 (m, IH), 2.09-2.07 (d, 2H), 1.92-173 (m, 2H), 1.66-1.52 (m, 3H), 1.43-1.39 (m, IH), 1.33-1.26 (m, IH), 1.02 (s, 3H), 1.0 (s, 3H).
  • Preparation 81 is prepared from preparation 80 in a manner similar to preparation 4. (O.95g, 99%): 1 H NMR (CDCl 3 ) 6 7.21-7.17 (t, IH), 6.84-6.82 (d, IH), 6.79-6.78 (t, IH), 676-6.73 (dd, IH), 3.79 (s, 3H), 2.98-2.93 (q, IH), 2.55-2.46 (m, IH), 2.13-2.09 (dd, 2H), 1.93-1.73 (m, 2H), 1.66-1.55 (m, 2H), 1.46-1.41 (m, IH), 1.33-1.27 (m, IH), 1.04 (s, 3H), 1.00 (s, 3H).
  • Preparation 82 is prepared from preparation 81 in a manner similar to preparation 5. (.72g, 81%): 1 H NMR (CDCl 3 ) ⁇ 8.06-8.04 (d, IH), 6.87 (s, IH), 6.84-6.81 (dd, IH), 3.87 (s, 3H), 3.21-3.17 (m, IH), 2.77-2.72 (m, IH), 2.55-2.47 (m, 2H), 2.28-2.22 (m, IH), 1.98-1.88 (m, IH), 1.21-1.13 (m, 4H), 0.98 (s, 3H), 0.79 (s, 3H).
  • Preparation 83 is prepared from preparation 82 in a manner similar to preparation 6. (.43g 49%): 1 H NMR (CDCl 3 ) ⁇ 8.16-8.14 (d, IH), 7.01-6.99 (d, 2H), 6.89-6.86 (m, 2H), 6.80-6.78 (d, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 3.61-3.60 (m, IH), 3.13-3.11 (m, IH), 2.56-2.51 (m, IH), 2.23-2.18 (m, IH), 1.84-1.77 (m, IH), 1.49-1.46 (d, 2H), 1.33-1.21 (m, 2H), 0.98 (s, 3H), 0.82 (s, 3H).
  • Preparation 84 is prepared from preparation 83 in a manner similar to preparation 7. (.34g, 55%): 1 H NMR (CDCl 3 ) ⁇ 7.51-7.49 (d, IH), 7.19-7.17 (d, 2H), 6.93-6.88 (m, 3H), 6.83-6.78 (m, 2H), 4.63-4.59 (m, IH), 3.83 (s, 3H), 3.82 (s, 3H), 2.90-2.85 (m, IH), 2.78-2.73 (m, IH), 2.43-2.40 (m,lH), 2.04-1.96 (m, IH), 1.52-1.45 (m, 2H), 1.38-1.34 (m, 2H), 1.26-1.24 (m, 2H), 0.82 (s, 3H), 0.79 (s,3H).
  • Preparation 85 is prepared from preparation 84 in a manner similar to preparation 8. (.3g 93%): 1 H NMR (CDCl 3 ) ⁇ 7.49-7.46 (d, 2H), 7.05-7.03 (d, IH), 6.89-6.86 (m, 3H) 6.69-6.66 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.15-3.12 (m, IH), 2.98-2.92 (m, IH), 2.33-2.28 (m, IH), 2.0-1.92 (m, Ih), 1.47-1.39 (m, 2H), 1.23-1.12 (M, 2H), 1.04 (s, 3H), 0.74 (s, 3H).
  • Preparation 86 is prepared from preparation 85 in a manner similar to preparation 9. (.3g, 99%): 1 H NMR (CDCl 3 ) ⁇ 7.17-7.15 (d, 2H), 7.03-7.01 (d, IH), 6.88-6.87 (m, IH), 6.83-6.81 (d, 2H), 6.80-6.65 (dd, IH), 3.75 (s, 3H), 3.74 (s, 3H), 3.10-3.08 (m, 3H), 2.83-2.76 (m, IH), 2.24-2.16 (m, 2H), 1.91-1.83 (m, IH), 1.04-1.0 (m, 2H), 0.94-0.80 (m, 2H), 0.76 (s, 3H), 0.66 (s, 3H).
  • Preparation 93 is prepared from preparation 92 in a manner similar to preparation 5. (0.9g, 97%): 1 H NMR (CDCl 3 ) ⁇ 6.99-6.96 (d, IH), 6.78-6.76 (d, IH), 3.84 (s, 3H), 3.82 (s, 3H), 3.41-3.35 (q, IH), 2.73-2.65 (m, IH), 2.6-2.46 (m, 2H), 2.44-2.36 (m, IH), 1.97-1.88 (m, IH), 1.85-1.69 (m, 2H), 1.55-1.47 (m, IH).
  • Preparation 94 is prepared from preparation 93 in a manner similar to preparation 71. (0.79g, 61%) : 1 H NMR (CDCl 3 ) ⁇ 7.08-7.06 (d, 2H), 6.97-6.95 (d, IH), 6.87-6.85 (d, 2H), 6.77-6.75 (d, IH), 3.83 (s, 3H), 3.79 (s, IH), 3.72-3.69 (d, IH), 3.54-3.48 (q, IH), 2.93-2.86 (m, IH), 2.56-2.47 ((m, IH), 1.85-1.58 (m, 4H), 1.5-1.4 (m, IH).
  • Preparation 95 is prepared from preparation 94 in a manner similar to preparation 7. (0.57g, 72%) : 1 H NMR (CDCl 3 ) ⁇ 7.30-7.23 (m, 2H), 6.92-6.89 (m, 2H), 6.78-6.68 (m, 2H), 4.97-4.95 (m, IH), 4.03-3.98 (m, IH), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.34-3.28 (m, IH), 3.0-2.93 (m, IH), 2.78-2.66 (m, IH), 2.50-2.38 (m, 2H), 1.83-1.76 (m, IH), 1.68-1.62 (m, 2H), 1.43-1.36 (m, IH).
  • Preparation 96 is prepared from preparation 95 in a manner similar to preparation 8. (0.2Og, 37%): 1 H NMR (CDCl 3 ) ⁇ 7.41-7.39 (d, 2H), 6.92-6.87 (m, 3H), 6.67-6.66 (d, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.48-3.46 (m, 2H), 2.89-2.22 (m, IH), 2.14- 2.06 (m, IH), 1.67-1.60 (m, IH), 1.53-1.42 (m, 4H).
  • Preparation 97 is prepared from preparation 96 in a manner similar to preparation 9. (0.19g, 94%): 1 H NMR (CDCl 3 ) ⁇ 7.24-07.22 (d, 2H), 6.88-6.85 (d, 2H), 6.66-6.65 (d, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.62-3.56 (m, IH), 3.13-3.08 (m, IH), 3.02- 2.97 (m, IH), 2.71-2.64 (m, IH), 2.60-2.52 (m, IH), 2.40-2.33 (m, IH), 1.53-1.23 (m, 5H).
  • Preparation 98 Preparation 98
  • Preparation 99 is prepared from preparation 98 in a manner similar to preparations 7 and 8.
  • 1 H NMR (CDCl 3 ): 7.43 (m, 2H), 6.9 (d, J 8.8 Hz, 2H), 6.85 (m, IH), 6.45(m, IH), 6.2 ( s, IH), 3.83 (s, 3H), 3.8 (m, 3H), 3.4-3 (m, IH), 2.2-1.95 (m, 3H), 1.7-1.4 (m, 4H).
  • Preparation 100 is prepared from preparation 99 in a manner similar to preparation 9.
  • Trifluoromethanesulfonic acid 8-methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b- hexahydro-lH-cyclopenta[a]naphthalen-6-yl ester
  • Preparation 106 is prepared from cyclohexene oxide and l-bromo-3,5- dimethoxybenzene in a manner similar to preparation 10.
  • Preparation 107 is prepared from preparation 106 in a manner similar to preparation 11.
  • Preparation 108 is prepared from preparation 107 in a manner similar to preparations 1 and 2.
  • Preparation 109 is prepared from preparation 108 in a manner similar to preparation 3.
  • Preparation 110 is prepared from preparation 109 in a manner similar to preparation 5. MS m/z 261 (M+ 1).
  • Preparation 111 is prepared from preparation 110 in a manner similar to preparation 6. MS m/z 367 (M+ 1).
  • Preparation 112 is prepared from preparation 111 in a manner similar to preparation 98. MS m/z 353 (M+l).
  • Preparation 113 is prepared from preparation 112 in a manner similar to preparation 7. MS m/z 353 (M-I).
  • Preparation 114 is prepared from preparation 113 in a manner similar to preparation 8. MS m/z 335 (M-I).
  • Preparation 115 is prepared from preparation 114 in a manner similar to preparation 9. MS m/z 337 (M-I).
  • Trifluoro-methanesulfonic acid 3-methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10- octahydro-phenanthren-1-yl ester
  • Preparation 116 is prepared from preparation 115 in a manner similar to preparation 101.
  • Preparation 117 is prepared from preparation 116 in a manner similar to preparation 103.
  • 1 H NMR (CDCl 3 ): 7.3 (m, 2H), 7.2 (s, IH), 6.93 (d, J 8.4 Hz, 2H), 3.92 (s, 3H), 3.88(s, 3H), 3.85 (s, 3H), 3.5-3.05 (m, 4H), 2.5 (m, IH), 2.05 (m, IH), 1.75 (m, IH), 1.7-1.05 (m, 6H).
  • Preparation 118 is prepared from preparation 117 in a manner similar to preparation 104.
  • 1 H NMR (CDCl 3 ) 7.3 (m, 2H), 6.95 (m, 4H), 4.77 (s, 2H), 3.87 (s, 3H), 3.88(s, 3H), 3.85 (s, 3H), 3.25 (s, IH), 3.15 (m, IH), 3.05 (m, IH), 2.9 (m, IH), 2.5 (m, IH), 2.05 (m, IH), 1.8-1.05 (m, 7H).
  • Preparation 119 is prepared from preparation 117 in a manner similar to example 13. MS m/z 365 (M-I).
  • Preparation 127 is prepared from preparation 123 in a manner similar to preparation 126.
  • Preparation 128 is prepared from preparation 124 in a manner similar to example 18. MS m/z 363(M+1).
  • Preparation 130 is prepared from preparation 123, using dimethylformamide as the electrophile, in a manner similar to preparation 126. MS m/z 351 (M+l).
  • Preparation 132 is prepared from preparation 131 in a manner similar to preparation 129.
  • Methanesulfonic acid 9-(4-methanesulfonyloxy-phenyl)-2-(3-methanesulfonyloxy- propyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-yI ester
  • Methanesulfonic acid 9-(4-methanesulfonyloxy-phenyl)-2-(3-methoxy-propyl)- 4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-yl ester
  • Preparation 134 is prepared in a manner similar to Example 16. MS m/z 523 (M+l).
  • Preparation 136 is prepared from preparation 135 in a manner similar to Example 1. MS m/z 337 (M-I). Preparation 137
  • Preparation 137 is prepared from preparation 130 in a manner similar to Example 1. MS m/z 321 (M-I).
  • Trifluoro-methanesulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-l,2,3,4,4a,10a- hexahydro-phenanthren-9-yl ester
  • Example 2 is prepared from preparation 18 in a manner similar to example 1.
  • Example 2 Separate example 2 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 3
  • Example 3 is prepared from preparation 27 in a manner similar to example 1.
  • example 3 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 4 Separate example 4 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 5 P-CS-Fluoro ⁇ -hydroxy-phenyO- ⁇ jSyojT ⁇ S ⁇ a ⁇ jlO-octahydro-phenanthren-S-ol
  • Example 5 is prepared from preparation 40 in a manner similar to example 1.
  • Example 6 is prepared from preparation 53 in a manner similar to example 1.
  • example 6 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 7 is prepared from preparation 63 in a manner similar to example 1.
  • example 7 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 9 9-(4-Hydroxy-phenyl)-7,7-dimethyl-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-ol
  • example 9 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 10 is prepared from preparation 97 in a manner similar to example 1. (0.067g, 40%): 1 H NMR (CDCl 3 ) ⁇ 7.19-7.17 (d, 2H), 6.82-6.79 (d, 2H), 6.55-6.54 (d, 2H), 4.59 (s, IH), 4.37 (s, IH), 3.55-3.49 (m, IH), 3.08-3.02 (m, IH), 2.98-2.93 (m, IH), 2.78-2.71 (m, IH), 2.65-2.57 (m, IH), 2.43-2.35 (m, IH), 1.48-1.25 (m, 5H).
  • Example 10 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 11 is prepared from preparation 102 in a manner similar to Example 1.
  • Example 12 is prepared from preparation 103 in a manner similar to Example 1.
  • Example 19 is prepared from preparation 115 in a manner similar to Example 1.
  • example 19 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 20 is prepared from preparation 118 in a manner similar to example 14. MS m/z 387, 385 (M + ).
  • example 20 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 21 is prepared from example 20 in a manner similar to example 16.
  • example 21 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 22 is prepared from preparation 117 in a manner similar to example 1.
  • example 22 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 23 is prepared from example 22 in a manner similar to preparation 104.
  • 1 HNMR (DMSO-J 6 ): 9.18 (s, IH), 8.95 (s, IH), 7.14 (d, J 8.8 Hz, 2H), 6.75 (m, 3H), 6.69 (s, IH), 4.45 (m, 2H), 3.15 (m, IH), 3.0 (m, IH), 2.9 (m, IH), 2.65 (m, IH), 2.4 (m, IH), 1.9 (m, IH), 1.7-0.9 (m, 7H). MS m/z 323 (M-I).
  • example 23 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 24 is prepared from example 20 in a manner similar to example 15.
  • 1 H NMR (DMSOd 6 ): 9.28 (s, IH), 9.21 (s, IH), 7.16 (d, J 8.4 Hz, 2H), 6.8 (s, IH), 6.74 (m, 3H), 3.97 (s, 2H), 3.15 (m, IH), 3.05 (m, IH), 2.9 (m, IH), 2.65 (m, IH), 2.4 (m, IH), 1.95 (m, IH), 1.65 (m, IH), 1.55 (m, IH), 1.4 (m, IH), 1.3-0.8 (m, 4H). MSm/z 332 (M- 1).
  • example 24 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 26 is prepared from preparation 121 in a manner similar to example 1.
  • Example 27 is prepared from preparation 123 in a manner similar to example 1.
  • Example 28 l-[3-Hydroxy-9-(4-hydroxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-2-yI]- ethanone
  • Example 28 is prepared from preparation 124 in a manner similar to example 1.
  • Example 30 is prepared from preparation 125 in a manner similar to example 1.
  • example 30 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 32 is prepared from preparation 126 in a manner similar to example 1.
  • example 32 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 33 is prepared from preparation 127 in a manner similar to example 1.
  • MS m/z 335 Separate example 33 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 34 is prepared from preparation 129 in a manner similar to example 1.
  • example 34 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 35 is prepared from preparation 132 in a manner similar to example 1.
  • Example 37 is prepared from example 35 in a manner similar to example 36.
  • Example 38 is prepared from example 35 in a manner similar to example 36.
  • Example 38 is prepared from example 35 in a manner similar to example 36.
  • example 40 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Methanesulfonic acid 9-(4-methanesulfonyloxy ⁇ phenyl)-2-(3 ⁇ methoxy- propyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-yl ester (0.044g, 0.084 mmol), 5N KOH ( 2Ml), and methanol (2 ml) and heat at 8O 0 C for 2 hours. Remove solvent in vacuo. Add ethyl acetate and 6N HCl. Wash organic layer with water, dry over anhydrous sodium sulfate and remove solvent in vacuo.
  • Example 43 is prepared from Example 40 in a manner similar to Example 1.
  • Example 44 is prepapred from preparation 136 in a manner similar to preparation 104.
  • example 46 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 48
  • Example 49 is prepared from preparation 142 in a manner similar to example 1.
  • Example 50 is prepared from preparation 146 in a manner similar to example 1.
  • example 52 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 56 is prepared from preparation 153 in a manner similar to example 1.
  • Example 58 into its enantiomers using the conditions described for the separation of example 1 into its enantiomers (examples IA and IB).
  • Example 59 is prepared from preparation 160 in a manner similar to example 1. (15.8 mg, 49%).
  • the competition ER binding assay is run in a buffer containing 50 mM N-[2- hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid (Hepes) pH 7.5, 1.5 mM EDTA, 150 mM NaCl, 10% glycerol, 1 mg/mL ovalbumin, 5mM DTT, 0.025 ⁇ Ci per well of 3 H- Estradiol (New England Nuclear #NET517 at 118 Ci/mmol, 1 mCi/mL), and 10 ng/well ER- ⁇ or ER- ⁇ Receptor (Pan Vera). Competing compounds are added at 10 different concentrations.
  • Non-specific binding is determined in the presence of 1 ⁇ M of E2 (17- ⁇ Estradiol, Sigma, St. Louis, MO).
  • the binding reaction (140 ⁇ L) is incubated for 4 hours at room temperature, then 70 ⁇ L of cold dextran coated charcoal (DCC) buffer is added to each reaction (DCC buffer is prepared by adding 0.75g of charcoal [Sigma] and 0.25g of dextran [Pharmacia] per 50 mL of assay buffer).
  • DCC buffer is prepared by adding 0.75g of charcoal [Sigma] and 0.25g of dextran [Pharmacia] per 50 mL of assay buffer).
  • the incubation plates are mixed for 8 minutes on an orbital shaker at 4°C and then centrifuged at 3,000 rpm for 10 minutes at 4°C.
  • Preferred compounds bind to the ER- ⁇ receptor with a Kj of less than 20 nM. More preferred compounds bind to the ER- ⁇ receptor with a Kj of less than 1 nM. Compounds that are selective to binding to the ER- ⁇ receptor compared to the ER- ⁇ receptor bind to the ER- ⁇ receptor with a lower Kj compared to the Ki for the ER- ⁇ receptor.
  • the compounds of examples 1-59 exhibit binding affinities (Ki) at the ER- ⁇ subtype in the range approximately 4->1000 nM and to the ER- ⁇ subtype in the range of approximately 0.2-500 nM.
  • the agonist activity of the compounds of the invention can be determined from assay(s) described in Harris, H. A.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Endocrinology, 143, p. 4172-4177 (2002).
  • ER- ⁇ agonists are evaluated for their effects on the growth of androgen-sensitive LNCaP human prostatic cancer (PCa) xenografts grown in intact sexually mature (5-6 weeks old) Hsd: Athymic Nude-nu (Athymic Nude) male mice. 2.0x10 ⁇ LNCaP tumor cells are injected bilaterally by the subcutaneous route into the pre-tracheal region of testicular intact male mice. Mice are castrated via the scrotal route to serve as the positive control group. Test compounds are administered once per day by subcutaneous or gavage administration at multiple dose levels in a volume of 0.2 ml to xenograft- bearing mice starting on the day following tumor injection.
  • PCa human prostatic cancer
  • Test compounds are reformulated weekly based on average group mean body weights.
  • the vehicle for these studies is 1% carboxymethyl cellulose (CMC) with 0.25% Tween 80.
  • CMC carboxymethyl cellulose
  • Tween 80 1% Tween 80.
  • Body weights and tumor measurements are recorded on a weekly basis and entered directly into a JMPTM (SAS; Cary, NC) spreadsheet from electronic caliper measurement.
  • Tumor volumes in mm ⁇ are calculated in JMP using the following formula: L x W x H x 0.5236.
  • Tumor and body weight responses for individual mice are recorded on a weekly basis. When LNCaP tumor volumes enter log-phase expansion, lesions are measured every 3-4 days.
  • SAS linear extrapolation model
  • a mouse BPH study is essentially performed as a modified version of the rat BPH study as described earlier (Eur J Endocrinol. 2004 Apr;150(4):591-60313).
  • CD-I male mice are single caged and housed for 1 week and treated with vehicle or compounds at various daily doses, given orally in a 1% Carboxymethylcellulose (CMC) + 0.25% Tween 80 in PBS, pH 6.8 formulation.
  • CMC Carboxymethylcellulose
  • Tween 80 in PBS, pH 6.8 formulation.
  • the animals are sacrificed using CO 2 , followed by blood collection using cardiac puncture. The animals are then subjected to necropsy to collect intact ventral prostate, seminal vesicle and/or testes to measure organ wet weight changes between treatment groups.
  • RNA later TM solution Total RNA is obtained using the RNeasy kit (Qiagen Corp.).
  • Specific Taqman primers for SGP-2 or clusterin, 18S ribosomal RNA (Applied Biosystems, Foster City, CA, Catalog # 4310893E) and smooth muscle myosin heavy chain (derived from Genebank sequence for rat NMJ313607) are used to quantify biomarker changes in these prostate tissues using real time PCR.
  • PCR primers mouse SGP-2 gi 192149 -6 IF CGCAGACCGGACTCCAGAT mouse SGP-2 gi 192149 -121R CCACGCACAGCAGGAGAAT mouse SGP-2 TaqMan " probe: mouse SGP-2 gi 192149 -81T CCAAGGAGGCCACGCCATGAA While the exemplified compounds of the present invention demonstrate significant lowering of ventral prostate weights compared to vehicle control according to this test, preferred compounds demonstrate a significant lowering in prostate weight at doses of 10 mg/kg/day or less.
  • a therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • the dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a therapeutically effective amount of a compound of Formula I is expected to vary from about 0.001 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts can be determined by one skilled in the art.
  • a compound of Formula I can be administered in any form or mode which makes the compound bioavailable in a therapeutically effective amount, including oral, inhalation, and parenteral routes.
  • compounds of Formula I can be administered orally, by inhalation of an aerosol or dry powder, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like.
  • Oral or inhalation administration is generally preferred for treatment of respiratory diseases, e.g. asthma.
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts, such as acid addition salts or base addition salts, for purposes of stability, convenience of crystallization, increased solubility and the like.
  • compositions of the compounds of Formula I are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solution, suspensions, or the like.
  • the compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations typically contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention may be determined by someone skilled in the art.
  • the tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • dosage unit forms may contain other various materials that modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1 % of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the compound of Formula I present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations can be determined by one of ordinary skill in the art.
  • the compounds of the present invention may also be administered by inhalation, such as by aerosol or dry powder. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the compounds of the present invention or a formulation thereof. Formulations for administration by inhalation of compounds of formula (I) may be delivered in single phase, bi-phasic, or tri-phasic systems. A variety of systems are available for the administration by aerosols of the compounds of formula (I). Dry powder formulations are prepared by either pelletizing or milling the compound of formula (I) to a suitable particle size or by admixing the pelletized or milled compound of formula (I) with a suitable carrier material, such as lactose and the like. Delivery by inhalation includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosols and dry powder formulations for administration by inhalation can be determined by one skilled in the art.
  • the compounds of the present invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Topical formulations may contain a concentration of the Formula I or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

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Abstract

L'invention concerne nouveaux composés tétraline agonistes du récepteur d'oestrogènes ß (ER-ß), des compositions pharmaceutiques de ceux-ci, et l'utilisation de ces composés pour traiter une maladie induite par ER-ß telle que la polyurie nocturne, l'uropathie obstructive, l'hypertrophie prostatique bénigne, l'obésité, la démence, l'hypertension, l'incontinence, le cancer du colon, le cancer de la prostate, la stérilité, la dépression, la leucémie, la maladie intestinale inflammatoire et l'arthrite.
PCT/US2006/004540 2005-02-15 2006-02-10 Tetralines substituees utilisees comme antagonistes selectifs du recepteur d'oestrogenes beta WO2006088716A1 (fr)

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US11/814,806 US8093302B2 (en) 2005-02-15 2006-02-10 Substituted tetralins as selective estrogen receptor-β agonists

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009047791A2 (fr) * 2007-09-24 2009-04-16 Reliance Life Sciences Pvt. Ltd. Antagoniste de signalisation de récepteurs de type toll (tlr)
US7585985B2 (en) 2003-04-21 2009-09-08 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
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US8063102B2 (en) 2009-03-13 2011-11-22 N.V. Organon Tetrahydronaphthalen-2-ol derivatives
JP2013545731A (ja) * 2010-10-27 2013-12-26 シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ 生物学的特性を賦与されたジテルペノイド誘導体
EP2786991A3 (fr) * 2008-08-27 2014-11-12 Corning Incorporated 2H-chromènes photochromes condensés en C5-C6 et leurs procédés de préparation
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US9623021B2 (en) 2007-01-22 2017-04-18 Gtx, Inc. Nuclear receptor binding agents
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US7585985B2 (en) 2003-04-21 2009-09-08 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7842822B2 (en) 2003-04-21 2010-11-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US9604931B2 (en) 2007-01-22 2017-03-28 Gtx, Inc. Nuclear receptor binding agents
US9623021B2 (en) 2007-01-22 2017-04-18 Gtx, Inc. Nuclear receptor binding agents
US9078888B2 (en) 2007-01-22 2015-07-14 Gtx, Inc. Nuclear receptor binding agents
WO2009047791A3 (fr) * 2007-09-24 2009-08-06 Reliance Life Sciences Pvt Ltd Antagoniste de signalisation de récepteurs de type toll (tlr)
WO2009047791A2 (fr) * 2007-09-24 2009-04-16 Reliance Life Sciences Pvt. Ltd. Antagoniste de signalisation de récepteurs de type toll (tlr)
EP2786991A3 (fr) * 2008-08-27 2014-11-12 Corning Incorporated 2H-chromènes photochromes condensés en C5-C6 et leurs procédés de préparation
JP2012520265A (ja) * 2009-03-13 2012-09-06 エム・エス・ディー・オス・ベー・フェー テトラヒドロナフタレン−２−オール誘導体
CN102272081B (zh) * 2009-03-13 2014-04-30 默沙东有限责任公司 四氢萘-2-醇衍生物
WO2010103095A1 (fr) 2009-03-13 2010-09-16 N.V. Organon Dérivés du tétrahydronaphtalèn-2-ol
CN102272081A (zh) * 2009-03-13 2011-12-07 欧加农股份有限公司 四氢萘-2-醇衍生物
US8063102B2 (en) 2009-03-13 2011-11-22 N.V. Organon Tetrahydronaphthalen-2-ol derivatives
JP2013545731A (ja) * 2010-10-27 2013-12-26 シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ 生物学的特性を賦与されたジテルペノイド誘導体
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
US9974776B2 (en) 2013-12-05 2018-05-22 Karo Pharma Ab Estrogen receptor beta agonists for use in treating mesothelioma
US20230210826A1 (en) * 2022-01-06 2023-07-06 The Curators Of The University Of Missouri Drug combination for treating obesity

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